1. Field of the Invention
The present invention relates to local delivery of radioactivity. The present invention also relates to localized inhibition of cell proliferation using radioactivity.
2. Brief Description of the Prior Art
The therapeutic use of radiation therapy to reduce the proliferation of rapidly dividing cells has evolved from the Bergonixc3xa9 and Tribondeau Law of radiobiology which states that proliferative cells are more radiosensitive than normal cells (Bergonixc3xa9 and Tribondeau, 1959, Radiat. Res. 11:587). Hence, radiation therapy can be used to reduce proliferation cells in a tumor. The Bergonixc3xa9 and Tribondeau principle needs not be limited to the treatment of malignant tumors, however. A number of clinical situations require the reduction of cell proliferation: treatment of heterotopic bone formation, prevention of cheloids and more recently the inhibition of intimal hyperplasia. Having discovered that smooth muscle cell proliferation is inhibited after irradiation, radiation therapy has thus been applied to reduce the restenosis process following coronary angioplasty.
Coronary angioplasty is actually a well-established technique for the treatment of obstructive coronary disease. More than 500,000 angioplasties are performed every year worldwide. However, two major problems remain unsolved.
The first problem is acute closure, reported to occur in up to 11% of the cases after balloon angioplasty (Dorros et al., 1983, Circulation 67:723-730). In that context, intracoronary stenting appears as an invaluable procedure for the treatment of extensive dissections occurring after angioplasty. As a scaffolding vessel wall support, it preserves adequate coronary opening and perfusion.
The second problem is restenosis which has been shown to occur in 30 to 50% of the cases. So far, drug therapy has shown limited results in reducing the extent of the phenomenon (Popma J J et al., 1991, Circulation 84:1426-1436). Intracoronary stents have been shown in randomized trials, to reduce restenosis from 42% to 32% in the Stress trial while from 32% to 22% in the Benestent trial (Fischman D L. et al., 1994, N. Engl. J. Med. 331:496-501; Serryus P W. et al., 1994, N. Engl. J. Med. 331:489-495). The beneficial effect of stenting is presumably due to a better vessel geometry after dilation, although stenting has been proved to induce more neo-intima formation than other devices in swine (Karas S P. et al., 1992, J. Am. Coll. Cardiol. 20:467-474). Indeed, swine has been recognized as a relevant animal model for restenosis although the rat and rabbit animal models are also widely used. Morphologically and hemodynamically the porcine coronary vascular system is very similar to the human coronary system. Reproducible intimal proliferation is obtained after balloon injury in the pig coronary arteries. Histologically, the proliferative response to balloon injury in the pig coronary is very similar to the response seen in pathological studies of humans (Schwartz et al., 1990, Circulation 82:2190-2200).
Balloon dilation leads to global vascular lesions which include mechanical deformation of the vessel, extensive destruction of the endothelium and immediate formation of thrombus. All of these act through vasoactive hormones, growth factors, circulating cells and presumably lipids on the media muscle cells. It is observed that smooth muscle cells are activated and migrate to the intima where after proliferation and matrix secretion, a xe2x80x9cneo-intimaxe2x80x9d is generated [Hamon et al., 1995, Eur Heart J 16(Suppl 1):33-48]. This observation led to the proposal of a cellular mechanism for restenosis (FIG. 1). The role of elastic recoil and vessel remodeling has also been recognized following angioplasty (Kakuta T. et al., 1994, Circulation 89:2809-2815). Finally, thrombus adhesion through growth factors liberation, also plays a major role in the activation cascade (Fager G. et al., 1995, Circ. Res. 77:645-650).
Until now, drug therapy has consistently been focused on proliferation and thrombus inhibitions (Popma J J et al., 1991, Ibid.). Unfortunately, no significant effects were observed in human coronary restenosis when the drugs were administered systemically (Popma J J et al., 1991, Ibid.). The lack of a sufficient local drug concentration is the most common advocated reason to explain the inability to reduce neointima formation in humans. The research has thus targeted the local delivery of different drugs to prevent restenosis (Lincoff A M et al., 1994, Circulation 90(4):2070-2084). New catheters are already available to deliver drugs locally after angioplasty and feasibility trials are being conducted (Fram D B et al., 1994, J. AM. Coll. Cardiol. 23:186A).
Although the genetic and molecular understanding of the different mechanisms involved in restenosis have also been greatly improved, due to its complexity, the clinical genetic treatment of restenosis is expected to be very expensive and not readily available for still some time (Bennet M R. et al., 1995, Circulation 92:1981-1993).
The use of radiotherapy to reduce neointima formation was thus identified as a possible solution to the restenosis problem. Three basic approaches utilizing radiotherapy have thus been proposed:
1) External Irradiation:
External delivery using Gamma or Beta irradiation, showed that, at the single high dose used, a decrease in hyperplasia is observed. However, some groups detected fibrosis or necrosis in the irradiated region (Schwartz R S. et al., 1992, J. Am. Coll. Cardiol. 19:1106-1113). Moreover, this type of approach encompasses the irradiation of a large field.
2) Radioactive Catheter:
Experiments carried out with endovascular irradiation at the high dose/rate of Beta or Gamma rays produced a significant reduction in neointimal formation. However, this positive effect seems to be accompanied by fibrosis of the vessel resulting in a loss of vascular function thereof, suggesting that in the long term such a type of treatment might be detrimental. Furthermore, the irradiation treatment at the time when peak proliferation potential of the smooth muscle cells occurs (i.e. 24-48 hours) would be at best impractical in a clinical situation. Moreover, arteries receiving higher doses showed an increase diameter suggesting that irradiation would affect vessel remodeling [Waksman R. et al., 1995, J. A. Coll. Cardiol. (Special Issue (February 95)]. Of note, Brenner et al., 1996 (Radiation Oncology Biol. Phys. 36: 805-809) showed that a single high dose does not inhibit restenosis. Also, it has been reported that a 18 Gy single irradiation, failed to show a significant reduction in restenosis.
2) Radioactive Stents:
The group of Fischell studied the effects of P32 stent wire on smooth muscle cells and endothelial cells proliferation in tissue culture (Fischell T A. et al., 1994, Circulation 90: 2956-2963; and U.S. Pat. No. 5,059,166 and 5,176,617). Titanium wire which was first impregnated with P31 and then activated in a fission reactor was used. The resulting radioactive stent is thought to be emitting Beta radiation, although contaminating a and y emissions are likely because of the impregnation method. The use of such a stent on muscle cells demonstrated a dose response curve of inhibition at linear activities. However, at the highest wire activity level, there was inhibition observed as far as 10.6 mm from the wire.
This degree of penetration suggests that the stent emitted Gamma rays and that the use thereof in vivo would not deliver the radiation specifically to the targeted site, since a significant amount of normal surrounding tissue would be irradiated. This issue, amongst others, was indeed raised by Crocker et al., 1995 (Circulation 92:1353). The ion implantation technique creates lattice defects in the metallic crystal structure resulting in stoichiometric modification. These defects can contribute to diffusion of ions (leeching) modification of surface potential and alterations in clinical properties. Consequently, this method of radioactivation can alter the biocompatibility of the stent surface and hamper human clinical use.
Radiotherapeutic treatments using radioactive stents showed a significant dose-dependent reduction in neointima formation; this suggested a delayed regeneration of endothelial cells. Together with the long-range irradiation of surrounding tissues, this type of stent can be foreseen as having detrimental effects, especially in the long term, on the integrity and functionality of the treated vessel and surrounding tissues.
As mentioned previously, a number of animal models have been used to assess the feasibility and elaborate the methods of radiation therapy to be applied to humans. Radiotherapy of cancer is currently routinely used in humans. However, local delivery of radioactivity has yet to show its full potential. Only a few studies on radiation therapy following angioplasty in humans have been performed. All experiments dealt with relatively high dose rates. Using Ir192 Gamma irradiation source which delivered 2000 cGy in durations lasting from 5 to 15 min [Condado J A. et al., 1995, J. Inv. Cardiol., 1995, 7(SupplC):25C; Condado J A. et al., 1995, J. AM. Coll. Cardiol., 1995, (Special Issue (February 95):288A], mild spasms occurred in the majority of the treated coronary arteries. However, with the group which received 2500 cGy, 7 out of 8 treated arteries developed aneurisms. In the group with 2000 cGy, out of 12 treated arteries 4 developed restenosis. Thus, side effects with significant potential health hazard were recorded.
The feasibility of radiation therapy to inhibit cellular proliferation is suggested by increasing data on the relative resistance of non actively proliferating cells versus their actively proliferating counterparts. The resistance of non actively proliferating cells to radiation treatment is only relative, however, as assessed by the inhibitory effect of radiation on endothelial cells, or the fibrosis or other side effects promoted by the radiotherapy.
Pure Gamma, pure Beta and mixed irradiations have been tested. Since the thickness of the arteries is in the mm range, Beta-irradiation is preferred over Gamma-irradiation in angioplasty-related applications, due to the known deeper effects of the latter (Waksman R. et al., 1995, Circulation 92:1383-1386). Obviously, Beta rays also present advantages concerning radioprotection. However, due to the limitations associated with the fixing of the isotope onto the support such as a stent (i.e. suitable isotopes, shelf life of the radioactive stent, production costs, etc.), the use of a Beta-isotope in such systems does not offer an optimal solution.
The question of half-life of the isotope used is of crucial importance from a practical, as well as from a biological point of view. It is generally understood that it is preferable to choose an isotope that would irradiate for the minimum during a time period sufficient to inhibit the proliferative activity of the targeted cells, thereby minimizing the irradiation of the surrounding tissues. It is known that in order for less than 1% of the total radioactivity of an isotope to remain requires the passing of 6 half-lives. However, the removal of the remaining 1% radioactivity will require a very long time if not an infinite amount of time. In the case of 32P for example, which has a half-life of 14 days, 84 days are required to bring the level of radiation below the 1% mark. In the treatment of restenosis, for example, as radioactivity will mainly target smooth muscle cell proliferation, the need to be effective throughout the replication stage (approximately 15 days) has to be taken into consideration. Thus, a significant proportion of the radioactivity will remain in place long after the proliferation stage of the smooth muscle cells. It follows that the current technology is limited since the total radiation dose is controlled solely by the half-life and quantity of the chosen isotope.
It should be noted that all systems designed for delivering radioactivity to a targeted region have been based on implantation of the radioisotope to or beneath the surface of a support such as a stent. These systems aim at minimizing or even abrogating any xe2x80x9cleechingxe2x80x9d of the radioactivity from the support (Fischell et al., 1995, Circulation 92:1353-54). It should also be understood that, to date, no local radiation delivery system permits a flexible calculation and control of the total dose in the patient.
It would be beneficial for the medical and research practitioners to provide them with a radioactivity local delivery system that would be more practical to use, would limit unnecessary exposure to normal surrounding tissues, and could permit a more precise control of the dose and the dose rate of irradiation of the targeted cells.
In accordance with an aspect of the present invention, there is provided a method for determining a coefficient of diffusion of a radioisotope in a radioisotope-containing implant structure to administer to a vascular region of a patient""s body a dose of radioactivity at a given dose rate, comprising:
calculating a relation between the coefficient of diffusion of the radioisotope in the implant structure and a coefficient of diffusion of the radioisotope in the vascular region of the patient""s body for at least one given period of time during which the radioisotope has to be released from the implant structure; determining the diffusion coefficient of the vascular region; and determining, from the diffusion coefficient of the vascular region and in connection with the above mentioned relation, the diffusion coefficient of the implant structure required to release the radioisotope within the given period of time.
In accordance with preferred embodiments:
the method comprises introducing the radioisotope in a coating of the implant structure;
calculating a relation comprises calculating the relation between the coefficient of diffusion of the radioisotope in the implant structure and the coefficient of diffusion of the radioisotope in the vascular region both for the at least one given period of time and in connection with a given thickness of the coating;
calculating a relation comprises building a graph of this relation between the coefficient of diffusion of the radioisotope in the implant structure and the coefficient of diffusion of the radioisotope in the vascular region for said at least one given period of time;
calculating a relation comprises building many graphs of the relation between the coefficient of diffusion of the radioisotope in the implant structure and the coefficient of diffusion of the radioisotope in the vascular wall for said at least one given period of time, each graph being associated to a given thickness of this coating;
Another aspect of the present invention relates to a method for calculating a quantity of radioisotope to be introduced in an implant structure in view of administering to a vascular region of a patient""s body a dose of radioactivity at a given dose rate, comprising: calculating a relation between a coefficient of diffusion of the radioisotope in the implant structure and a coefficient of diffusion of the radioisotope in the vascular region of the patient""s body for at least one given period of time during which the radioisotope has to be released; determining the diffusion coefficient of the vascular region; determining, from the diffusion coefficient of the vascular region and in connection with the relation, the diffusion coefficient of the implant structure required to release the radioisotope within said given period of time; and calculating the quantity of radioisotope from the diffusion coefficient of the vascular region and the diffusion coefficient of the implant structure.
Preferably:
the implant structure is a stent having a plurality of struts for implantation in a blood vessel of the patient""s body, and the method further comprises optimizing a spacing between pairs of adjacent struts in the direction of blood flow in a vascular wall of the blood vessel, this vascular wall constituting the vascular region; and
the method further comprises combining the radioisotope with a chelating agent to form molecules, and introducing these molecules in the implant structure.
The present invention further relates to a helical stent to be implanted in a blood vessel of a patient""s body, wherein the helical stent has a plurality of successive struts, contains a radioisotope, and has a given coefficient of diffusion of the radioisotope in the stent. The pairs of adjacent struts are separated by a spacing which increases in a direction of blood flow in a vascular wall of the blood vessel in order to make more uniform the distribution of the radioisotope in the vascular wall.
According to advantageous embodiments:
the helical stent comprises a coating containing the radioisotope, this coating being of predetermined thickness and having the given coefficient of diffusion of the radioisotope; and
the coefficient of diffusion of the radioisotope is related to the coefficient of diffusion of the radioisotope in the vascular wall of the blood vessel.
The foregoing and other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of a preferred embodiment thereof, given by way of example only with reference to the accompanying drawings.